Vitamin D promotes the differentiation of prostate cancer (PCa) cells, maintains the differentiated phenotype of prostate epithelial cells, and can induce prostate cancer cell death, raising the possibility that vitamin D deficiency over time promotes the progression of subclinical PCa to clinical disease. This is particularly relevant to men WHO ARE DEFICIENT IN CIRCULATING (SERUM) VITAMIN D [<20 NG/ML 25(OH)D3]. These considerations support the use of vitamin D3 as a chemopreventive agent, especially in SUBJECTS WITH HYPOVITAMINOSIS D. We hypothesize that a daily dose of vitamin D3 (4,000 IU) taken for one year by Veterans diagnosed with low- risk, early-stage PCa, who are eligible for active surveillance AND ARE DEFICIENT IN CIRCULATING (SERUM) VITAMIN D [<20 NG/ML 25(OH)D3]will: a) result in a measurable decrease of serum PSA levels in a significant number of enrolled subjects, and b) be associated with a stabilization or improvement of their PCa pathology, as assessed through histologic examination of prostate tissue biopsy specimens (Gleason score and percent of positive biopsies) obtained at the end of the study, as part of their standard medical care for active surveillance. This VA Merit application proposes to conduct a randomized, placebo-controlled clinical study aimed at measuring the efficacy of vitamin D3 (4000IU/day) supplementation in Veterans diagnosed with early-stage prostate cancer, who elect to have their disease monitored through active surveillance (before considering definitive therapy) AND ARE DEFICIENT IN CIRCULATING (SERUM) VITAMIN D [<20 NG/ML 25(OH)D3]. The main objectives of this proposed clinical study are as follows: 1) To determine whether a daily supplement of 4,000 IU of vitamin D3 taken for twelve months will result in a measurable and significant decrease of serum PSA levels in Veterans diagnosed with low-risk, early stage PCa (Gleason score d6, PSA d10, clinical stage T1C or T2a), who elect to have their disease monitored through active surveillance for at least one year AND ARE DEFICIENT IN CIRCULATING (SERUM) VITAMIN D [<20 NG/ML 25(OH)D3]. 2) To determine in enrolled Veterans the pathology status of their PCa by analyzing prostate tissue biopsy specimens at the end of the study (Gleason score and percentage of positive biopsies), and by comparing them with those obtained before enrollment in this study, as part of their standard medical care. The implementation of these proposed studies will allow us to assess whether vitamin D3 supplementation can be utilized as a chemopreventive regimen in Veterans diagnosed with low- risk, early stage PCa, and provide a useful addition to active surveillance. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Vitamin D promotes the differentiation of prostate cancer cells, maintains the differentiated phenotype of prostate epithelial cells, and can induce prostate cancer cell death, raising the possibility that vitamin D deficiency over time promotes the progression of subclinical prostate cancer to clinical disease. We propose to conduct a clinical study aimed at measuring the efficacy of vitamin D3 (4000IU/day) supplementation in Veterans diagnosed with low-risk, early-stage prostate cancer, who elect to have their disease monitored through active surveillance. The successful completion of this proposed clinical study will allow us to determine whether correcting vitamin D deficiency [<20 ng/mL 25(OH)D3 at time of enrollment] in Veterans diagnosed with early- stage prostate cancer will prevent progression of their disease and improve their prognosis.